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Naphthaline lactam derivative and application thereof in propagation suppression of tumor cells

A technology of tumor cell proliferation and naphthalene lactam, applied in the field of medicinal chemistry, can solve the problems that the inherent structure of naphthalene lactam is not easy to modify, the number of naphthalene lactam derivatives is limited, etc., and achieve good activity and selectivity

Inactive Publication Date: 2009-12-16
DALIAN UNIV OF TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] However, based on the inherent structure of naphthalene lactam, it is not easy to modify. Although it has a wide range of and good biological activities, the number of naphthalene lactam derivatives that have been reported is still limited.

Method used

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  • Naphthaline lactam derivative and application thereof in propagation suppression of tumor cells
  • Naphthaline lactam derivative and application thereof in propagation suppression of tumor cells
  • Naphthaline lactam derivative and application thereof in propagation suppression of tumor cells

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Synthesis of 2-[(1-propargyl-benzo[c,d]indole)-2(1H)-ylidene]malononitrile (derivative 1):

[0035] (1) 1.69g naphthalene lactam (0.01mol), 0.6g malononitrile (0.01mol), 1.1mLPOCl 3 Add it to a 25mL two-necked bottle, add 15mL of toluene, heat to 100°C under magnetic stirring, and react at constant temperature for 4 hours, pour the reaction solution into methanol, and directly suction filter after cooling to obtain a brown solid crude product. After vacuum drying, the crude product was separated by column chromatography to obtain 1.82 g of yellow spongy crystals with a yield of 83%. Melting point: >300°C.

[0036] ESI-HRMS (m / z): Calculated: 217.064, Found: 217.0639.

[0037] 1 HNMR (d6-DMSO, 400MHz): δ (ppm): 5.30 (s, 1H), 7.21 (d, J = 7.2Hz, 1H), 7.58 (t, J 1 =7.6Hz,J 2 =8.0Hz, 1H), 7.68(d, J=8.0Hz, 1H), 7.83(t, J 1 =8.0Hz,J 2 =7.2Hz, 1H), 8.17(d, J=8.0Hz, 1H), 8.55(d, J=8.0Hz, 1H).

[0038]

[0039] (2) Dissolve 0.217g derivative 13 (1mmol) in 10mL DMF, add...

Embodiment 2

[0044] Synthesis of 2-[(1-bromoethyl-benzo[c,d]indole)-2(1H)-ylidene]malononitrile (derivative 2):

[0045]

[0046] Dissolve 0.217g derivative 13 (1mmol) in 10mL anhydrous acetonitrile, add 0.2g K 2 CO 3 , 1mL of dibromoethane, heated to reflux under magnetic stirring, the reaction was complete after 5h, directly evaporated in vacuum to obtain a solid crude product, washed with water and dried in vacuum to obtain a yellow solid. Purified by column chromatography to obtain 0.175 g of yellow crystals with a yield of 80% and a melting point of 232.3°C.

[0047] ESI-HRMS (m / z): Calculated: 323.0058, Found: 323.0067.

[0048] 1 HNMR (CDCl3, 400MHz): δ (ppm): 3.83 (t, J 1 =6.4Hz,J 2 =6.8Hz, 2H), 4.85(t, J 1 =6.4Hz,J 2 =6.8Hz, 2H), 7.25(d, J=7.6Hz, 1H), 7.61(t, J 1 =8.0Hz,J 2 =7.6Hz, 1H), 7.70(d, J=8.0Hz, 1H), 7.82(t, J 1 =8.0Hz,J 2 =7.6Hz, 1H), 8.15(d, J=8.4Hz, 2H), 8.71(d, J=7.6Hz, 1H).

Embodiment 3

[0050] Synthesis of 2-{[(2-aminoethyl)-benzo[c,d]indole]-2(1H)-ylidene}malononitrile (derivative 3):

[0051]

[0052] Dissolve 0.217g derivative 13 (1mmol) in 10mL DMF, add 0.134gNaOCH 3 (2.4mmol), the temperature was raised to 100°C, and after half an hour of reaction, 0.243g of bromoethylamine hydrobromide (1.2mmol) was added, and the reaction was refluxed for 4h. The cooled reaction solution was poured into 150 mL of ice water, the aqueous phase was extracted with dichloromethane, and the anhydrous MgSO 4 After drying the organic phase, the crude product was obtained by rotary evaporation. Purified by column chromatography to obtain 0.176 g of yellow crystals with a yield of 68% and a melting point of 213.2°C.

[0053] 1 HNMR (d6-DMSO, 400MHz): δ (ppm): 1.84 (t, NH 2 , 2H), 2.54(m, NCH 2 CH 2 N, 2H), 2.87 (m, NCH 2 CH 2 N, 2H), 6.32(d, J=7.6Hz, 1H), 6.54(t, J 1 =7.6Hz,J 2 =8.8Hz, 1H), 7.54(d, J=8.8Hz, 1H), 7.34(d, J=7.6Hz, 1H), 7.35(t, J 1 =7.6Hz,J 2 =7.2Hz,...

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Abstract

The invention relates to a naphthaline lactam derivative and application thereof in the propagation suppression of tumor cells, belonging to the technical field of pharmaceutical chemistry. The naphthaline lactam derivative takes naphthaline lactam as a parent, and a derivative with high biological activity base groups, such as acetylene bonds, nitrile groups, amine groups or acylamide structures, and the like is obtained respectively by synthetic methods of firstly using different alkylogen hydrocarbon to carry out dehydrogenating condensation to two-position carbonyl and a compound with active methylene, introducing different electrophilic substitution base groups by six positions and then carrying out substitution to the active hydrogen of one-position imine. An experiment of the naphthaline lactam derivative for the propagation suppression of tumor cells selects a tetrazolium reduction method and is carried out aiming at 7721 human body liver cancer cells, MCF-7 human body mammary cancer cells, Hela human body cervical carcinoma cells or BGC-823 human body stomach cancer cells; and a result indicates that the naphthaline lactam derivative has favorable activity and selectivity in the propagation suppression of the tumor cells.

Description

technical field [0001] The invention relates to a class of naphthalene lactam derivatives and their application in inhibiting tumor cell proliferation, belonging to the technical field of medicinal chemistry. Background technique [0002] Naphtholactam has special biological activity due to its special lactam structure, which has always attracted the interest and attention of bioorganic chemists. Mari'a L.Lo'pez-Rodri'guez et al. interacted with the N-substituted naphthalene lactam with optimized structure and the 5-HT7R receptor, and the pKi values ​​were all less than 7.3 (mari'a L.Lo'pez-Rodri'guez , et al. J. Med. Chem. 2003, 46, 5638-5650). Yansong Gu et al. introduced alkyl-substituted 1,4-cycloheptanediamine at the 6-position of naphthalene lactam, and synthesized a compound for regulating 5-HT 2 Naphtholactam series derivatives for C receptor disorder or deficiency (Gu et al. U.S. Patent 6,667,303B1). [0003] However, based on the inherent structure of naphthalen...

Claims

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Application Information

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IPC IPC(8): C07D209/90A61K31/403A61P35/00
Inventor 李晓莲张英利
Owner DALIAN UNIV OF TECH
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